Janet Dafoe's Open Medicine Foundation Interview with Robert Phair

Janet Dafoe interviewed Robert Phair for the Open Medicine Foundation.

Janet Dafoe has been doing an informative series of videos on the Open Medicine Foundation’s work. Her patient-centered approach – she often interrupts a researcher engaging in “research speak” to clarify in simple English what’s going on – is refreshing.

At the end of 2022 and the beginning of 2023, her two-part series with Robert Phair – the creator of the IDO Metabolic Trap hypothesis for ME/CFS – focused on his latest approach – the Itaconate Trap Hypothesis.

The Itaconate Shunt hypothesis – with its potential ability to explain so much in ME/CFS (energy production problems, strange metabolomic results, post-exertional malaise, brain fog, immune issues) – provided a compelling idea.

After the Open Medicine Foundation provided vital support to the development of the hypothesis, Vinod and Neeru Khosla’s Amar Foundation in San Jose, CA jumped in to provide funding to test it in Chris Armstrong’s lab at the Open Medicine Foundation’s Melbourne Collaboration at the University of Melbourne in Australia.

Vinod Khosla, a co-founder of Sun Microsystems, and his wife, Neeru, created the Amar Foundation in 1987. In 2011, they were one of the early adopters to sign onto the Giving Pledge created by Warren Buffet, and Melinda and Bill Gates, which commits wealthy individuals to give away the majority of their wealth during their lifetimes or in their wills.

The Mind Meld

Robert Phair PhD is the cofounder of Integrative Bioinformatics Inc., a computational biology consulting firm that has been taking a systematic approach to the modeling of biological systems for over 20 years. Phair got interested in ME/CFS when he met a neighbor with the disease at Stanford and began working with Ron Davis to find solutions for ME/CFS in 2016.

In late 2019, during discussions with Chris Armstrong – the Open Medicine Foundation’s metabolomics expert – and since 2020, the leader of the Open Medicine Foundation’s Melbourne Collaboration, Phair and Armstrong puzzled over the “ammonia problem” in ME/CFS. Armstrong and others found that ME/CFS patients’ cells were preferentially using amino acids instead of the body’s preferred sources – glucose or fatty acids.

Amino acids are not a preferred energy substrate for a couple of reasons. Among them is that they have this pesky nitrogen atom attached to them that needs to be taken care of. The body usually eliminates the nitrogen using a variety of “safe” forms, but ME/CFS studies have not found increased levels of these safe forms. That suggested  “unsafe” forms of nitrogen such as ammonia or peroxynitrite were building up. These two highly reactive compounds can, among other things, wreak havoc in the energy production systems that power our cells.

Chris Armstrong and the Hunt for the Metabolic Underpinnings of ME/CFS

During the pandemic, when Phair had shifted his work to understanding the innate immune system, he uncovered an innate immune enzyme called CAD which he felt might help explain the ammonia mystery. With support from the Open Medicine Foundation and the Amar Foundation, Phair got to work. Using a modeling tool created by Integrative Bioinformatics Inc., Phair had a potential answer by Sept. 2021 to the amino acid/ammonia problem in ME/CFS – and the Itaconate Trap hypothesis was borne.

The hypothesis is particularly compelling because it potentially ties together an infectious insult, a hit to the energy production system, brain fog, post-exertional malaise, and immune dysfunction.

The Itaconate Shunt (or Trap) Hypothesis Pt. I

Citric acid cycle

The important thing to note in this diagram are the areas just outside the circle where NADH and FADH2 are produced. They provide the electrons that power the electron transport chain where ATP is produced. The itaconate shunt blocks them from being produced.

The first thing to know is that a variety of transformations occur within the citric acid, or Krebs, cycle in the mitochondria which ultimately produce substances like NADH and FADH2 which provide the electrons that power the electron transport chain to produce ATP.

It all begins outside the mitochondria, though, with energy substrates the Krebs, or TCA, cycle uses to produce NADH/FADH2. The cycle’s preferred energy sources are glucose and fatty acids. Notice the central role that acetyl-CoA plays in the cycle.

  • Glycolysis converts glucose to pyruvate, which gets converted to acetyl-CoA
  • Fatty acids – get into Krebs cycle via conversion to acetyl-CoA

The Krebs cycle can use amino acids as well. Amino acids, though, get into the Krebs cycle in an entirely different way and at a different point.

An Infection – Energy Disruption Link 

So far, so good, but then comes the itaconate shunt – which is initiated by our old “friend”, the innate immune system. The innate immune system is an ancient immune response found in all vertebrates that quickly scrambles to hold an infection in check long enough for the adaptive immune response to mount a hopefully devastating pathogen-specific attack a couple of days later. The innate immune system can also be activated by stress, injuries, or environmental toxins.

One of the many factors that the innate immune system produces is called cis-aconitate decarboxylase, or CAD. In just the second step of the Krebs cycle, CAD interrupts it – sending plunging it down a different path – one which effectively turns off its ability to produce abundant amounts of energy.

First CAD alters cis-aconitate to itaconate, which then gets catalyzed by an enzyme in the Krebs cycle called STK (succinate thiokinase) into something called Itaconyl CoA.

Itaconate shunt

The itaconate shunt – in blue – bypasses the energy-producing portions of the Krebs cycle.

Remember acetyl-CoA? The Krebs cycle normally breaks it up – allowing the cycle to move forward. In the itaconate shunt, though, STK loads CoA onto itaconate thus turning the Krebs cycle into an energy sink instead of an energy producer. Instead of the Krebs cycle producing ATP, ATP is actually lost. The itaconate shunt, then, effectively bypasses the energy-producing steps of the Krebs cycle.

This does not necessarily mean that energy production is completely stopped – some cis-aconitase is probably still getting through – but it’s probably severely inhibited.
Our cells have produced a backup energy system, however, called the GABA shunt.


  • Janet Dafoe interviewed Robert Phair twice on his Itaconate Shunt hypothesis for the Open Medicine Foundation at the end of last year and in the beginning of this year. This blog is from the first interview.
  • The Itaconate Shunt hypothesis is compelling because it potentially ties together an infectious insult, a hit to the energy production system, brain fog, post-exertional malaise, and immune dysfunction. First funded by the Open Medicine Foundation, work testing the hypothesis is now being funded by the Amar Foundation created by Vinod and Neeru Khosla.
  • The roots of the hypothesis began during discussions between Robert Phair and Chris Armstrong, the leader of the Open Medicine Foundation’s Melbourne Collaboration in Australia. Armstrong and others had found that people with ME/CFS were preferentially using amino acids instead of better fuels like glucose and fatty acids to power their cells.
  • The increased utilization of amino acids should have produced high levels of nitrogenous byproducts in their blood. The fact that they weren’t present suggested that the safe breakdown of amino acids wasn’t happening and that toxic byproducts like ammonia were being produced instead.
  • Phair glommed onto a possible reason for this during the coronavirus pandemic. He found that an immune enzyme called CAD that is produced during an infection can produce something called an “itaconate shunt” which causes the energy-producing cycle in the mitochondria to short-circuit.
  • In fact, it’s worse than that. Not only does the energy-producing cycle (the TCA/Krebs/citric acid cycle) get whacked but the itaconate shunt turns it into an energy sink. Instead of producing energy, it actually draws energy from the cell.
  • It seems bizarre to turn off or inhibit energy production during an infection but it has a purpose. Because the pathogens that infect cells use the cell’s energy to produce more pathogens it’s thought that the itaconate shunt temporarily shuts down the cell to restrict pathogen replication long enough for the next phase of the immune system – the adaptive immune system – to gear up to wipe out the pathogen.
  • Phair proposes that instead of lasting for a few days, ih ME/CFS the itaconate shunt becomes permanently turned on.
  • Our cells have produced a backup energy system, however, called the GABA shunt – which could explain the preferential use of amino acids by ME/CFS patient’s cells. Unlike the other parts of the Krebs/Citric acid/TCA cycle the GABA shunt uses amino acids for energy and is not affected by the itaconate shunt.
  • The GABA shunt, though, produces only about 40% of the normal energy produced by our cells – and it comes with a problem – it leaves behind nitrogen byproducts that need to be broken down. As noted earlier, studies suggest that our amino acids are not being broken down safely – possibly resulting in high levels of ammonia – a toxic byproduct that can, among others, affect energy production.
  • The hypothesis is being tested by Chris Armstrong at the Open Medicine Foundation’s Melbourne Center and by at least one other group of researchers.
  • In Pt II Health Rising will cover why the itaconate shunt may be becoming chronic in ME/CFS and where we are now with the hypothesis.

A Defense Strategy

The great question that arises is: why? Why would we have hardwired into our cells a way for the innate immune system to turn off energy production during an infection? The shunt must serve a purpose, and it does. It’s a defense strategy. As the itaconate shunt whacks the energy production of our cells, it’s also doing a number on the pathogens that have infected our cells. They need energy, after all, to reproduce – energy they get from our cells. With the cell’s energy centers shut down, the pathogens have trouble replicating – giving our adaptive immune system a chance to rev up and attack them with pathogen-specific immune hunters.

While Phair doesn’t mention it in his talk, this energy shutdown during an infection seems reminiscent of Robert Naviaux’s Dauer hypothesis. It also seems to jive with the idea of “sickness behavior” in which symptoms like fatigue, brain fog, and other flu-like symptoms immobilize an individual and keep her/him from spreading an infection.

The idea is that instead of staying on for a couple of hours, or at most a couple of days, the shunt gets turned on permanently in ME/CFS.

The Workaround – the GABA Shunt

But what about the preferential use of amino acids to produce energy we’re seeing in ME/CFS? We’ve had no answer to that. It turns out, though, that the Itaconate Shunt hypothesis provides a convenient answer for that – although it’s not a pretty one.

As we’ve seen, both glucose and fatty acid metabolism in the Krebs cycle depend on CoA – the substance that the itaconate shunt essentially takes out of the picture.

Of course, our cells have a workaround – a kind of failsafe to ensure that at least some energy is still being produced. An alternative to the normal workings of the Krebs cycle – called the GABA shunt – is available.

The GABA shunt uses four enzymes already present in the Krebs cycle to complete the cycle in the absence of CoA and ultimately produce ATP. It’s only about 40% as efficient as the CoA-powered Krebs cycle, but you do eventually get some ATP out of it.

With the GABA shunt, we have a possible answer to the strange pattern of the preferential amino acid utilization issue seen in ME/CFS. If the Itaconate Shunt hypothesis is correct, our cells are mostly turning to the only available substrate left – an intermediate amino acid called glutamate – to power their engines.

The hits don’t stop with energy production, however. Using high levels of glutamate to feed our mitochondria has its consequences – among them leaving the brain high and dry regarding its essential energy substrate – glutamate – potentially producing brain fog, problems with memory and learning, etc.



Chris Armstrong is checking whether higher than normal levels of ammonia are being produced in ME/CFS.

With the GABA shunt, we get to what started this whole thing off – ammonia! Both the Itaconate Trap hypothesis and ME/CFS metabolomic studies suggest that our cells are probably loaded with glutamate. If the hypothesis is correct, amino acids are the only really usable energy substrate we have left.

That, however, leaves us in a tricky situation. When we exert ourselves and use up our ATP, something called ADP is left over. (Instead of adenosine triphosphate (ATP) we’re left with adenosine diphosphate (ADP).) ADP is the normal byproduct of energy production.

ADP, though, triggers the breakdown of glutamate, which results (in part) in the production of ammonia – a highly toxic substance. This is not usually a problem because: a) the Krebs normally runs mostly on glucose and fatty acids and doesn’t produce much ammonia, and b) healthy people can safely break it down anyway. Because ME/CFS cells may be top-loaded with ammonia, and perhaps because people with ME/CFS have trouble breaking it down, Phair and Armstrong believe high levels of ammonia may be present.

This is “one of the many ways” Phair believes that ME/CFS may get going. Chris Armstrong is designing carbon 13 tracers to see if the itaconate shunt has become chronic in ME/CFS.

Note that the itaconate shunt is not a hypothesis – we know it happens in the early stages of an infection. The Itaconate Shunt or Trap hypothesis, though, proposes that it has become chronic in ME/CFS. The next part of Janet Dafoe’s interview with Robert Phair, in Pt. 2, tackles why he believes the shunt may have become chronic in ME/CFS.

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